Insulin resistance contributes to the pathogenesis of several disease states including obesity and noninsulin-dependent diabetes mellitus (NIDDM). We have investigated the insulin receptor gene in patients with genetic forms of insulin resistance to gain insight into biochemical defects that give rise to disease. Five classes of mutations have been identified: 1. Impaired receptor biosynthesis, due to either decreased levels of insulin receptor mRNA and/or premature chain termination mutations. In fact, we have recently identified a patient who is homozygous for a total deletion of the insulin receptor gene. 2. Impaired transport of receptors to the plasma membrane, due to missense mutations in the extracellular domain of the receptor. 3. Decreased affinity of insulin binding. 4. Decreased activity of the insulin receptor tyrosine kinase. Unlike most mutations in the extracellular domain, most mutations in the tyrosine kinase domain exert a dominant negative effect to cause insulin resistance. At least two molecular mechanisms may account for this dominant negative effect. First, by dimerizing with normal receptors, mutant receptors may inhibit tyrosine kinase activity of the oligomer. Second, by binding substrates, mutant receptors may inhibit phosphorylation of intracellular proteins by normal receptors. 5. Accelerated receptor degradation. Several mutations cause multiple defects in receptor function. For example, the Val-382 mutation in the extracellular domain impairs transport of receptors to the plasma membrane, but also inhibits the ability of insulin to activate receptor tyrosine kinase. The Glu-1135 mutation in the catalytic loop of the tyrosine kinase domain not only inactivates the tyrosine kinase, but also impairs post- translational processing and transport to the plasma membrane. Work is underway to develop transgenic mice with insulin resistance due to mutations in the insulin receptor gene by using homologous recombination to inactivate the insulin receptor gene in embryonic stem cells. We have recently succeeded in obtaining chimeric mice.